Over the past two and a half decades there has been an epidemic growth in the rates of obesity in the United States. Approximately one-third of the country is now clinically obese and two-thirds are overweight (1), putting many at risk of increased risk of developing insulin resistance and contracting chronic diseases such as cardiovascular disease (CVD), type II diabetes (T2D), several types of cancer, stroke, gallbladder disease, and obstructive sleep apnea (2, 3).
One factor known to play an essential role in the development of obesity-induced insulin resistance is inflammation. Obesity is associated with higher systemic inflammation (4), and inhibiting essential inflammatory pathways has been shown to completely dissociate obesity from insulin resistance (5-8). Thus, it is not altogether surprising that many of the more effective anti-diabetic treatments are also anti inflammatory in nature. One such class of drugs is the thiazolidinediones (TZDs), which include rosiglitazone (AVANDIA) and pioglitazone (ACTOS). The TZDs insulin-sensitizing actions are mediated mainly through the nuclear receptor peroxisome proliferator-activated receptor γ (PPAR γ) (9), which acts in a number of direct and indirect distinct mechanisms to reduce inflammation. As a key regulator of adipocyte differentiation, PPAR γ agonists increase the number of adipocytes in the subcutaneous adipose tissue region (9), thereby preventing adipocytes in visceral adipose tissue from being hypertrophic and dysfunctional (10). The hypertrophy and inflammation of visceral adipocytes is thought to be one of the main initiating steps in the development of obesity induced chronic inflammation (11). Hypertrophic adipocytes, in addition to secreting fatty acids, which can wind up in unwanted places such as the liver, heart, blood vessels, and skeletal muscle, also become apoptotic and recruit pro-inflammatory macrophages into white adipose tissue (11, 12). PPAR γ agonists inhibit monocyte migration and pro-inflammatory cytokine secretion from macrophages by blocking the activation of the pro-inflammatory transcription factor nuclear factor-κB (NF-κB) (13-15). The practical use for these compounds actually beyond diseases associated with obesity and insulin resistance as PPAR γ activation has shown potential for treating various forms of cancer (i.e., lung, breast, colon) (16), multiple sclerosis (17), malaria (18), airway inflammation (19, 20), and autoimmune diseases (21-24), including intestinal inflammation, Crohn's disease, ulcerative colitis (25-27), arthritis (28), and dermatitis (29).
Despite their beneficial effects, TZDs are associated with a number of health risks, such as weight gain, fluid retention, and congestive heart failure that have limited their potential for use in many of the conditions described above (16). There are also side-effects associated with the biguanides, (i.e., metformin or Glucophage), which are also used currently to improve insulin sensitivity, such as lactic acidosis (30). It is in this context in which the present inventors began to investigate the ability of a natural compound, abscisic acid (ABA), to activate PPAR γ without potentially dangerous side-effects. In their initial studies, they found that ABA increases PPAR γ activity in vitro and, when supplemented into high-fat diets, significantly improves glucose tolerance and prevents adipose tissue inflammation in db/db mice (17). These effects were mitigated in mice deficient in PPAR γ in immune cells (18). In all the studies performed, in which the longest period of ABA administration took place over 7 months, there were no side effects associated with the ABA-supplementation (17, 18).
Since the inventors' initial work, there have been studies showing that ABA increases pancreatic insulin secretion through a cyclic AMP (cAMP)/protein kinase A (PKA)-dependent mechanism (19), thus further elucidating ABA's mechanism of action in mammalian cells.